Certificate of correction



United States Patent '3-HYDROXY-3{(MGNOCARBOCYCLIC ARYL) HY- DROXYMETHYL] TROPANES AND PREPARA- TION THEREGF Sydney Archer, Bethlehem, and Malcolm R. Bell, North Greenbush, N.Y., assignors to Sterling Drug lnc., New York, N.Y., a corporation of Delaware N0 Drawing. Original application Apr. 30, 1958, Scr. No. 731,857. Divided and this application Jan. 8, 1959, Scr. No. 1,388

11 Claims. (Cl. 260-292) wherein R represents hydrogen, a lower-aliphatic hydrocarbon, monocarbocyclic aryl substituted lower-alphatic hydrocarbon, or a monocarbocyclic arylamino substituted lower-aliphatic hydrocarbon radical, R represents hydrogen, a lower-alkoxy radical, the hydroxy radical or a carboxylic acyloxy radical, and R represents a loweralkyl radical.

In the above general Formula I, R represents a hydrogen atom or a substituent selected from lower-aliphatic hydrocarbon, monocarbocyclic aryl substituted loweraliphatic hydrocarbon, and monocarbocyclic arylamino substituted lower-aliphatic hydrocarbon radicals. When R stands for a lower-alphatic hydrocarbon radical it represents saturated or unsaturated radicals, i.e., lower-alkyl, lower-alkenyl, or lower-alkynyl having from one to about eight carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tertiary-butyl, hexyl, octyl, vinyl, l-propenyl, 2-propeny1 (allyl), 2-butenyl, ethynyl, propargyl, and the like. I

When R represents a monocarbocyclic aryl substituted lower-aliphatic hydrocarbon radical, it stands for the same type of lower-aliphatic radicals as described above substituted by a phenyl radical or a phenyl radical having one or more substituents such as hydroxy, fluoro, chloro, brorno, iodo, nitro, amino, lower-alkoxy, loweralkylamino or lower-carboxylic acylamino. A preferred class of monocarbocyclic aryl radicals comprises phenyl and phenyl substituted by from one to three substituents selected from hydroxy, fluoro, chloro, bromo, iodo, nitro, amino, lower-alkoxy, lower-alkylamino and lower-carboxylic acylamino. Thus, R can represent such groups as benzyl, 2-phenylethyl, 3-phenylpropyl, cinnamyl, p-aminophenethyl, p-methoxyphenethyl, p-chlorophenethyl, 3,4,5- trimethoxyphenyl, and the like.

When R represents a monocarbocyclic arylamino substituted lower-aliphatic hydrocarbon radical, the monocarbocyclic aryl and lower-hydrocarbon moieties have the same meanings as given above, but are separated by an imino grouping, NH-, and R in this instance represents such groups as 2-phenylaminoethyl, 3-phenylaminopropyl, 3-phenylamino-2-propenyl, 2-(p-aminophenylamino) ethyl, and the like.

relates to com- 3,073,829 Patented Jan. 15, 1963 "ice In the above general Formula I, R represents a hydrogen atom or a lower-alkoxy, hydroxy or carboxylic acyloxy radical. The lower-alkoxy radicals have preferably from one to about four carbon atoms, thus including such radicals as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. The carboxylic acyloxy radicals are preferably derived from carboxylic acids having from one to about ten carbon atoms, and having a molecular weight less than about 250. Representative of the acryl radicals which can be present are lower-alkanoyl radicals, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl, decanoyl, and the like; carboXy-lower-alkanoyl radicals, e.g., succinyl (flcarboxypropionyl); cycloalkyl-lower-alkanoyl radicals, e.g., B-cyclopentylpropionyl, fi-cyclohexylpropionyl, and the like; monocarbocyclic aroyl radicals, e.g., benzoyl, p-toluyl, p-nitrobenzoyl, 3,4,5-trimethoxybenzoyl, and the like; and monocarbocyclic aryl-lower-alkanoyl or -alkenoyl radicals, such as phenylacetyl, p-phenylpropionyl, cinnamoyl, and the like.

ln'the above general Formula I, R" represents a hydrogen atom or a lower-alkyl radical, the latter having preferably from one to about six carbon atoms, thus including such radicals as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

The preparation of the compounds of the invention is delineated by the following flow-sheet:

VI (R=H or lower-alkoxy) 1-2 hours (room temp.)

VIII (R=H or lower-alkoxy) ,carboxy-8-R-nortropane (IV).

NOH

IX (R=H or lower-alkoxy) X (R=H or lower-alkoxy) or-n-ornont coon" I (R=H or lower-alkozy) An 8-R-nortropan-3-one (II) is treated with hydrogen cyanide to give the cyanohydrin, 3-hydroxy-3-cyano-8-R- nortropanefl ll). The latter is hydrolyzed in acid medium to the corresponding carboxylic acid, 3-hydroxy-3- The acid (IV) is esterified with a lower-alkanol under acid conditions to the loweralkyl ester, 3-hydroxy-3-carbo-lower-alkoxy-8-R- nortropane (V). p

The hydroXy ester (V) is subjected to reaction with phenyllithium or a monocarbocyclic arylmagnesium halide, e.g., phenylmagnesium halide, or a 3-lo'wer-alkoxy derivative thereof, and the intermediate organometallic complex is hydrolyzed to produce a 3-hydroXy-3-[bis- (monocarbocyclic aryl)hydroxymethyl]-8-R-nortropane (VI). The reaction is carried out under anhydrous conditions in an inert solvent such as ether, benzene, toluene HUI-HOAC 100C.

of the like, and takes place at room temperatures, al-

through gentle heating may be applied if desired to accelerate the reaction.

The glycol (VI) when treated at room temperature with zinc chloride and acetic anhydride first dehydrates to give an epoxide of a 3-bis(monocarbocyclic aryl)methylene- S-R-nortropane (VII) and then rearranges to a 3-(monocarbocyclic aryl)-3-(monocarbocyclic aroyl)-8-R-nortropane (VIII). The epoXide (VII) can be isolated if the reaction mixture is worked up after about one to two hours, whereas rearrangement to the ketone (VIII) is essentially complete if the reaction mixture is allowed to stand for at least about ten hours before working up.

The next step is the conversion of the ketone (VIII) to its oxime, a 3-(monocarbocyclic aryl)-3-(a-isonitrosomonocarbocyclic arylrnethyl)-8-R-nortropane (IX) which is accomplished by heating the ketone with an acid-addition salt of hydroxylamine in the presence of a base. Preferred bases are weak organicbases such as pyridine and the reaction is carried out in an inert solvent such as ethanol, at a temperature between about 50 C. and 150 C., in which case the oxime is obtained directly in the form of its acid-addition salt.

The conversion of the oxime (IX) to a 3-(monocarbocyclic aryl)-3-carboxy-8-R-nortropane (X) is efiected by heating a solution of the oxime in acetic acid saturated with dry hydrogen chloride at a temperature between about 50 C. and 150 C. The transformation involves a Beckrnann rearrangement followed by cleavage of the intermediate anilide having the grouping --CONHC H R' in the 3-position, as confirmed by the isolation of aniline from the reaction mixture in the case where R is H.

The final step is an esterification of the acid (X) by treating it with a lower-alkanol in the presence of a strong acid, giving a 3-(monocarbocyclic aryl)-3-(carbo-loweralkoxy) -8-R-nortropane (I). The esterification takes place at room temperature or above.

The ketones of Formula VIII can be reduced catalytically or with lithium aluminum hydride to produce the corresponding hydroxy compounds, 3-(monocarbocyclic aryl -3- (monocarbocyclic aryl-hydroxymethyl) -8-R-nortropanes (XI) The compounds of Formula XI in the form of their acidaddition or quaternary ammonium salts are useful as anticholinergic agents.

An alternative approach to the compounds of the invention of Formula I is set forth in the following flowsheet (R" represents a lower-alkyl radical and R has the meaning given above):

XII

Li or XVI (R=I-I or lower-alkoxy) A 3-hydroxy-3-carbo-lower-alkoxy-8-R-nortropane of structure V is converted to the corresponding amide, 3- hydroxy-3-carbamyl-8-R-nortropane (XII), by treating with sodium amide in liquid ammonia. The amide X II is then subjected to a Grignard reaction with a'loweralkylmagnesium halide, the reaction stopping readily at structure VI and they can be represented by a single formula as follows:

CHs-OH-CHz OH Y wherein R represents hydrogen or a lower-alkoxy radical, Y represents a lower-alkyl or 3-R' phenyl radical, and R has the same meaning as given above.

The diol XIV is then converted to the desired 3-(monocarbocyclic aryl)-3-l0wer-alkanoy1-8-R-nortropane (XV) by treatment with zinc chloride and acetic anhydride at room temperature for ten or more hours, analogously to the conversion of VI (or VII) to VIII. The structure XV belongs to the same class of. compounds as structure XVIII and they can be represented by a single formula as follows:

XVIII wherein R represents hydrogen or a lower-alkoxy radical, Y represents a lower-alkyl or 3-R'-phenyl radical and R has the same meaning as given above.

The ketone XV is then converted to its oxime, a 3- (monocarbocyclic aryl) -3-( 1-isonitroso-lower-alkyl) -8- R-nortropane (XVI), by treatment with hydroxylamine, analogously to the conversion of VIII to IX. The struc- .ture XVI belongs to the same class of compounds as structure IX and they can be represented by a single formula as follows:

wherein R represents hydrogen or a lowcr-alkoxy radical, Y represents a lower-alky1 or a 3-R-pheny1 radical, and R has the same meaning as given above.

The oxime XVI is then subjected to the Beckmann rearrangement by heating it with hydrochloric and acetic acid at about 100 C., analogously to the conversion of IX to X, and the structure X is again produced.

The ketones of Formulas VIII and XV, wherein R represents hydrogen or the methyl radical, when in the form of their acid-addition salts exist largely in the tautomeric carbinolamine form, viz.:

the compounds wherein R represents hydrogen by reacting the latter with a halide, RX, wherein X is halogen, in the presence of a basic condensing agent, or acid-acceptor, such as sodium carbonate, sodium methoxide, sodium amide, sodium hydride, or the like. This N-alkylation procedure can be efiected at any stage in the synthesis, but preferably upon compounds I or V (R=H).

The compounds of the invention wherein R represents hydrogen can be prepared directly from nortropinone (II, R H) according to the above flow-sheet. Alternatively, they can be prepared by reacting a compound wherein R is methyl with cyanogen bromide and then treating the resulting N-cyano compound with acid or base.

The compounds of Formulas I, VIII, X and XV wherein R is a hydroxy radical are prepared by dealkylation of the corresponding compounds wherein R is a loweralkoxy radical. The dealkylation is carried out by heating the alkoxy compound with hydrogen bromide or hydrogen iodide in Water or acetic acid solution, or with pyridine hydrochloride or hydrobromide at about 200 C. If a compound of Formula I where R is hydroxy or acyloxy is desired, the dealkylation is preferably carried out on a compound of Formulas VIII, X or XV Where R is lower-alkoxy, and the resulting phenolic compound carried through the necessary subsequent steps to produce I (R' is OH). The compounds wherein R is a carboXylic acyloxy radical are prepared by esterifying the compounds wherein R is hydroXy by reacting the latter with the appropriate acid anhydride or acid halide.

The compounds of Formulas VI to X, inclusive, XII to XVI, inclusive, and I can exist in two stereochemical forms depending upon the spatial arrangement of the groups at Q, with respect to the remainder of the molecule. The sequence of steps shown in the first flowsheet leads to compounds which will be designated the ti-series. The other stereochemical series, to be designated the ct-series can be reached by treating the glycol VI with acetic anhydride in the absence of zinc chloride which leads to the epoxide VII of the tit-series. The epoxide VII of the Ot-SEIIES can then be carried through the same series of reactions to produce the compounds VIII, IX, X and I of the ot-series.

The novel compounds disclosed herein are useful in the free base form or in the form of acid-addition or quaternary ammonium salts, said salts also being within the purview of the invention. The preferred type of salts are pharmacodynamically acceptable salts, that is, salts whose anions are relatively innocuous to an animal organism in pharmacodynamic doses of the salts, so that the beneficial physiological properties inherent in the free base are not vitiated by side-effects ascribable to the anions. Appropriate acid-addition salts are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, citric acid, lactic acid, and tartaric acid. The quaternary ammonium salts are obtained by the addition of esters having a molecular weight less than about 200 to the free base form of the compounds. A preferred class of esters comprises alkyl, alkenyl or aralkyl esters of inorganic acids or organic sulfonic acids, and include such compounds as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, Z-hydroxyethyl bromide, allyl chloride, allyl bromide, methyl sulfate, methyl benzene sulfonate, methyl p-toluenesulfonate, benzyl chloride, benzyl bromide, and substituted benzyl halides, such as p-chlorobenzyl chloride, p-nitrobenzyl chloride, o-chlorobenzyl chloride, p-methoxybenzyl chloride, and the like.

The acid-addition salts are prepared either by disolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

The quaternary ammonium salts are prepared by mixing the free base and the alkyl, alkenyl or aralkyl ester in an organic solvent. Heating can be used to facilitate the reaction, although salt formation usually takes place readily atroom temperature. The quaternary ammonium salt separates directly or can be obtained by concentration of the solution.

Although pharmacodynamically acceptable salts are preferred, all acid-addition salts are within the scope of our invention. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is not desired as the final product, as for example when the salt is formed for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmacodynamically acceptable salt by ion exchange procedures. All crystalline salts are also useful as characterizing derivatives of the free bases.

The molecular structures of the novel compounds herein disclosed are established by their mode of synthesis and corroborated by the correspondence of calculated and found values for the elementary analyses for representative examples. The structures are further confirmed by ultraviolet and infrared spectral data proving the presence of the various functional groups.

The compounds of our invention having the general Formula I possess valuable pharmacodynamic properties, in particular, analgesic activity. For example, when tested intraperitoneally in rats by the Bass-Van der Brook modification of the DAmour-Smith method, 3-phenyl-3-carbethoxytropane hydrochloride [1; R is CH R is H, R" is C H B-series], was found to be approximately two and one-quarter times as active as meperidine hydrochloride as an analgesic. The former compound has an intravenous toxicity (LD in rats of 126:1.6 mg./kg. of body weight, and is very well tolerated by adult rhesus monkeys when administered intramuscularly in doses of 12 and 18 rug/kg. No depression of the respiratory rate or convulsions were observed in monkeys following administration of 3-phenyl-3-carbethoxytropane hydrochloride at doses as high as 18 mg./kg., whereas meperidine hydrochloride caused slight tomoderate respiratory depression of one to three hours duration in monkeys when administered intramuscularly in single, daily doses of 6.4 and 12.8 rug/kg.

The compounds of Formula I can be prepared for use by formulation in the same manner as meperidine, e.g., in aqueous or aqueous-ethanol menstruum, or in solid form, e.g., tablet or powder. The tablet formulation can be prepared using conventional excipients, and the powder can be compounded in capsule form. These preparations can be administered orally or, in the case of aqueous preparations, intramuscularly, intraperitoneally or intravenously.

The intermediates of Formulas VI-X and related compounds of Formula XI also possess pharmacological utility, for example anticholinergic or ganglionic blocking activity, and they can be prepared for use in the same manner as atropine or hexamethonium, e.g., as isotonic aqueous solutions for subcutaneous or intramuscular injection, or as tablets for oral administration.

The following examples will further illustrate the invention without being limited thereby.

addition was complete. The reaction mixture was stirred and refluxed for one hour, then cooled and treated with 300 ml. of water. The solid material which precipitated was removed by filtration and washed with ether. The dark red filtrates were decolorized with activated charcoal, dried over anhydrous sodium sulfate, and the resulting solution was treated directly with an excess Ogf alcoholic hydrogen chloride which caused separation of a nearly colorless crystalline powder. The latter was collected and dried at 60 C. in a vacuum oven for fifteen hours, giving 167 g. of 3-(diphenylhydroxymethyl)pseudotropine hydrochloride, M.P. 279.5-280.5 C. (decomposition) (corrected) after two recrystallizations from a methanol-ether mixture.

Anal.-Calcd. for C H NO HCl: C, 70.08; H, 7.28; Cl, 9.85. Found: C, 69.99; H, 7.39; Cl, 9.74.

A sample of the hydrochloride was treated with aqueous sodium carbonate, and the resulting free base was collected and recrystallized three times from hexane, giving 3- (diphenylhydroxymethyl)pseudotropine, M.P. 1 16-117 C. (uncorr.).

Anal.-Calcd. for C I-1 N0 2 C, 77.99; H, 7.79; .N, 4.33. Found: C, 77.93; H, 7.85; N, 4.29.

EXAMPLE 2 3-Benzhydrylideneiropane Epoxide [VII; R is CH;,, R is H, fl-series] Fused, powered zinc chloride (10 g.) was added all at once to a stirred suspension of 10 g. of 3-(diphenylhydroxyrnethyl)pseudotropine hydrochloride (Example 1) in 25 ml. of acetic anhydride at room temperature. Within fifty minutes the reaction mixture became homogeneous. After stirring for eighty minutes the dark brown solution was poured into a solution of 25 g. of sodium hydroxide in 200' ml. of water. The tan colored solid which separated was collected, dried and extracted with 250 ml. of boiling hexane. Upon evaporation of the extract to a volume of ml. and cooling there separated 4.7 g. of crystalline powder, M.P. 155-166" C. Concentration of the filtrate gave an additional 1.0 g., M.P. 161 C. The crops were combined and recrystallized from 30 ml. of boiling methanol to give 4.3 g. of 3- benzhydrylidenetrop-ane epoxide in the form of colorless plates, M.P. 166-166.5 C. (uncorr.).

AnaL-Calcd. for C H NO: C, 82.55; H, 7.59; N, 4.59. Found: C, 82.32; H, 7.65; N, 4.04.

The hydrochloride salt of 3-benzhydrylidenetropane epoxide was prepared by addition of an excess of alcoholic hydrogen chloride to an ethereal solution of the free base. The hydrochloride salt had the M.P. 27-6277 C. (dec.) (corn) when recrystallized from a methanol-ether mixture.

Anal.-Calcd. for C H NO.HCl: C, 73.77; 7.07; N, 4.10. Found: C, 73.48; H, 6.74; N, 4.04.

Neither B-benzhydrylidenetropane epoxide in carbon tetrachloride solution or its hydrochloride in a potassium bromide pellet exhibited carbonyl or hy-droxyl type absorption in the infrared specturm. The ultraviolet spectrum of the free base showed an extinction coeflicient of 13,400 and a maximum at 220 m plus weak absorption peaks at 250-260 mm.

EXAMPLE 3' 3-Phenyl-3-Benzoyltropane [VIII; R is CH R is H, B-series] (A) METHOD 1 [FROM 3-(DIPHENYLHYDROXY METHYL)PSEUDOTROPINE] Fused, powdered zinc chloride (98 g.) was added all at once toa stirred suspension of 98 g. of 3-(diphenylhydroxymethyl)pseudotropine hydrochloride (Example 1) in 250 ml. of acetic anhydride. The reaction vessel was cooled in an ice-water bath since the initial reaction was mildly exothermic. After stirring for one hour, the clear, dark brown solution was left at room temperature forsixty-three hours and then poured into a solution of 250 g. of sodium hydroxide in two liters of water with cooling. The solid material which separated was collected and extracted once with one liter of methylene dichloride. The filtrate was extracted three times with 200 ml. portions of methylene dichloride. The methylene dichloride extracts were dried and concentrated, and the residual oil crystallized from 600 ml. of hexane. The 48.5 g. of 3 phenyl-3-benzoyltropane thus obtained had the MP. 121- 122.5 C. (uncorr.) when recrystallized from 700 ml. of hexane.

Anal.Calcd. for C H NO: C, 82.55; H, 7.59; N, 4.59. Found: C, 82.87; H, 7.43; N, 4.57.

The hydrochloride salt of 3-phenyl-3-benzo-yltropane was obtained by treating an ether solution of a sample of the free base with an excess of alcoholic hydrogen chloride. The hydrochloride had the M.P. 249-25 1 C. (corn) when recrystallized from absolute ethanol.

Anal.Calcd. for C 1-1 NOl-ICl: C, 73.77; H, 7.07; Cl, 10.37. Found: C, 73.50; H, 6.98; Cl, 10.13.

The methiodide salt of 3-phenyl-3-benzoyltropane was prepared by treating an acetone solution of the free base with an excess of methyl iodide. The methiodide salt separated directly from solution and had the MI. 233.5- 237.5 C. (corn).

Anal.-Calcd. for C H INO: C, 59.06; H, 5.87; I, 28.37. Found: C, 59.17; H, 5.60; 1, 28.19.

The methiodide salt of 3-phenyl-3-benzoyltropane was found to have an anticholinergic activity 6.8% that of atropine sulfate. Its intravenous toxicity in mice (ALD was 9 mg./kg. of body weight.

(B) METHOD 2 [FROM 3-BENZHYDRYLIDENE- TROPANE EPOXIDE] EXAMPLE 4 3-Phenyl 3-(PhenyZisonitrosomcthyI)'Tropahe Hydrochloride [1X3 R is CH R is H, ,B-series] A mixture of g. of 3-phenyl-3-benzoyltropane (Example 3) and 10 g. of hydroxylamine hydrochloride in 25 ml. of pyridine and 75 ml. of absolute alcohol was refluxcd for fifteen hours. During this time the very insoluble oxime hydrochloride separated directly from the reaction mixture. The reaction mixture was cooled and the solid product collected by filtration, washed with ethanol and water and dried, giving 11.0 g. of 3-phenyl-3-(phenylisonitrosomethyl)tropane hydrochloride, MP. 327 C. (dec.) (uncorr.).

AnaL-Calcd. for cg Hg Nzolic/li C, H, N, 7.85. Found: C, 70.52; H, 6.86; N, 7.72.

EXAMPLE 5 3-PhenyI-S-Carboxytropane Hydrochloride [X; R is CH R is H, fl-series] A suspension of 10 g. of 3-phenyl-3-(phenylisonitro'somethyl)tropane hydrochloride (Example 4) in 75 ml. of acetic acid at 0 C. was saturated with dry hydrogen chloride gas. The solution was enclosed in a pressure bottle and heated on a steam bath for seventy minutes. At the end of this period the bottle was cooled, opened, and the solvent was evaporated in vacuo on a steam bath.

. The residue was dissolved in 50 ml. of warm methanol,

and 200 m1. of ether was added to cause separation of a 10 solid product. The latter was collected and recrystallized from 75 ml. of methanol and 130 ml. of ether, giving 4.5 g. of 3-phenyl-3-carboxytropane hydrochloride, MP. 224-225 C. (dec.) (corn) after a second recrystallization from the same solvents.

Annl.Calcd. for C H NO HCI: C, 63.93; H, 7.16; Cl, 12.58. Found: C, 63.80; H, 7.30; Cl, 12.55.

It was found that in the preceding preparation the pressure bottle could be dispensed with and the reaction accomplished by heating the reaction mixture at C. for two hours at atmospheric pressure while passing in dry hydrogen chloride.

in another run, aniline was isolated from the mother liquors by steam distillation, thus proving that the starting oxime had undergone a Beckmann rearrangement, followed by cleavage of the intermediate amide.

EXAMPLE 6 3-Phenyl-3-Carbethoxytropane Hydrochloride [1; R is CH R is H, R is C 11 B-series] A solution of 1.0 g. of 3-phenyl-3-carboxytropane hydrochloride (Example 5) in 40 ml. of absolute ethanol was saturated with dry hydrogen chloride and allowed to stand at room temperature for six days. The reaction mixture was then concentrated in vacuo, and the solid residue was recrystallized from 15 ml. of absolute ethanol and ml. of anhydrous ether, giving 0.9 g. of 3-phenyl- S-car-bethoxytropane hydrochloride in the form of colorless needles, M.P. 187-191 C. (dec.) (corr.).

Aiml.-Calcd. for C H NO HCl: C, 65.90; H, 7.81; Cl, 11.49. Found: C, 65.82; H, 7.81; Cl, 11.28.

By replacement of the ethanol in the preceding preparation by methanol, l-propanol, Z-propanol, l-butanol or l-hexanol, there can be obtained, respectively, 3-pheny1- 3-carbomethoxytropane hydrochloride [1; R is CH R is H, R is CH:-;]; 3-phenyl-3-carbopropoxytropane hydrochloride [1; R is CH R is H, R is (CH CH 3-phenyl-3-carboisopropoxytropane hydrochloride [1; R is CH R is H, R is CH(CH 3-phenyl-3-carbobutoxytropane hydrochloride [1; R is CH R is H, R is (CH CH or 3-phenyl-3-carbohexoxytropane hydrochloride [1; R is CH R is H, R is (CH CH The methobromide salt of 3-phenyl-3-earbethoxytropane was prepared by treating an acetonitrile solution of the free base with an excess of methyl bromide. The product separated directly from the solution and had the MP. 206207.5 C. (uncorr.) after recrystallization from an isopropyl alcohol-ether mixture.

Anal.Calcd. for C H NO Br: C, 58.19; H, 7.12; Br, 21.70. Found: C, 58.44; H, 7.13; Br, 21.63.

3-phenyl-3-carbethoxytropane hydrochloride can be reacted with a molar equivalent amount of a base, e.g., sodium hydroxide, to give the free base, 3-pheny1-3- carbethoxytropane, which in turn can be reacted with hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, lactic acid, quinic acid, methanesulfonic acid, methyl iodide, allyl bromide, benzyl bromide, or o-chlorobenzyl chloride to give, respectively, the hydrobromide, hydriodide, sulfate (or bisulfate), phosphate (or acid phosphate), lactate, quinate, methanesulfonate, methiodide, allobromide, benzobromide, or o-chlorobenzochloride salts.

EXAMPLE 7 3-Benzlzydrylidenetropane Epoxide Hydrochloride upon there separated 20 g. of tan crystalline solid. Re-

crystallization of the latter material from 40 ml. of absolute methanol and 350 ml. of ether gave 3-benzhydryl- Anal.-Calcd. for C H NO: C, 82.55; H, 7.59.

Found: C, 82.10; H, 7.71.

A mixed melting point and comparisons of the infrared spectra of the 3-benzhydrylidenetropane epoxide (wseries) just described and the 3-benzhydrylidenetropane epoxide of the Er-series described above in Example 2 indicated that the two compounds were ditferent. The infrared spectrum exhibited no absorption characteristic of a carbonyl or hydroxyl group. The ultraviolet spectrum had a maximum at 219 m with an extinction coefficient of 12,700 plus weak absorption at 250-260 mg.

hours, then cooled and poured into excess aqueous sodium hydroxide. The product was extracted with methylene dichloride and the extracts were decolorized with activated charcoal, dried and concentrated. The residual oil was boiled with 100 ml. of hexane, filtered, and the filtrate cooled to give additional solid which was removed by filtration. The second filtrate was concentrated, and the residue was dissolved in ether and treated with an excess of alcoholic hydrogen chloride. A gum separated which upon warming with acetone formed a crystalline solid. The latter was recrystallized from a methanolether mixture to give 3-phenyl-3-benzoyltropane in the form of colorless needles, M.P. 312 C. (dec.) (uncorr.).

Anal.Calcd. for C H NO.HCl: C, 73.77; H, 7.07; CI, 10.37. Found: C, 73.90; H, 704; C1, 10.11.

The ultraviolet spectrum of 3-phenyl-3-benzoyltropane (wseries) showed extinction coefficients of 10,300 and 336 and maxima at 249 and 320 mg, respectively. The infrared spectrum exhibited a strong band at 6.00 2.

EXAMPLE 3-phenyl-3-carboxytropane [X; R is CH R is H, aseries] can be prepared from 3-phenyl-3-(phenylisonitrosomethyl)tropane (ix-series) and acetic acid saturated with hydrogen chloride according to the manipulative procedure described above in Example 5.

EXAMPLE 11 3-phenyl-3-carbethoxytropane [I; R is CH R is H, R 5

1s C H wseries] can be prepared from 3-phenyl-3-carboxytropane (ix-series) and hydrogen chloride in ethanol according to the manipulative procedure described above in Example 6.

EXAMPLE 12 3-[Di(m-Anisyl)Hydroxymethyl]Pseudotropine [VI; R is CH R is OCH -m-anisyl-magnesium bromide (prepared from.187 g. of

m-anisyl bromide and 25 g. of magnesium) in 900 ml. of ether over a period of fifteen minutes. The reaction mixture was stirred and refluxed overnight. The reaction mixture was worked up according to the procedure described above in Example 1, giving 54.7 g. of 3-[di(n1- anisyl)hydroxymethyl]pseudotropine as the hydrochloride salt. The latter had the melting point 236-237 C. (dec.) (uncorr.) when recrystallized from isopropyl alco hol and an isopropyl alcohol-ether mixture.

Alml.Calcd. for C H NO .HCl: C, 65.78; H, 7.20; CI, 8.44. Found: C, 65.84; H, 6.86; Cl, 8.55.

EXAMPLE 13 3-( m-Anisyl -3-(m-Anisoyl) T ropane [VIII; R is CH R is OCH A stirred, cooled suspension of 54.7 g. of 3-[(rnanisyl)hydroxymethyl]pseudotropine hydrochloride in 150 ml. of acetic anhydride was treated all at once with 150 g. of fused, powdered zinc chloride, and the mixture was stirred at room temperature for fifteen hours. Following a procedure the same as that described above in Example 3, part A, there was obtained 44 g. of 3-(manisyl)-3-(m-anisoyl)tropane in the form of a brown oil. The infrared spectrum of this compound in chloroform solution exhibited a strong peak at 6.02 characteristic of an aromatic ketone. This product was used in the next reaction without further purification.

EXAMPLE 14 3 m-A m'syl -3 m-Anisyl Isonitrosomethyl] Tropane Hydrochloride [IX; R is CH R is OCH A mixture of 44 g. of 3-(m-anisyl)-3-(m-anisoyl)tropane (Example 13), 44 g. of hydroxylamine hydrochloride, ml. of pyridine and 400 ml. of absolute alcohol was refluxed for nineteen hours. Upon cooling to 0 C. there separated a solid product which was collected by filtration, Washed with 200 ml. of absolute ethanol, and dried, giving 22.5 g. of 3-(m-anisyl)-3-[(m-anisy1)isonitrosomethylJtropane hydrochloride, which upon recrystallization from water had the M.P. about 295 C. (dec.) (uncorr.).

AllllL-CfilCd. for C23H23N203.HCll N, 6.72. Found: N, 6.71.

EXAMPLE 15 3- (m-Anz'syl) -3-Cdrboxytr0pane Hydrochloride A suspension of 5.0 g. of 3-(m-anisyl)-3-[(m-anisyl)- isonitrosomethyfltropane hydrochloride (Example 14) in 250 ml. of acetic acid was heated on a steam bath for two hours while a slow stream of dry hydrogen chloride was passed into the reaction mixture. The reaction mixture was then evaporated to dryness, the residue dissolved in 90 ml. of n-propyl alcohol, and the solution was filtered and treated with 9 ml. of triethylamine and ml. of acetone. After standing overnight at room temperature there had formed 2.4 g. of crystalline 3-(m-anisyl)-3-carboxytropane, M.P. 235 C. (dec.) (uncorr.). The latter material was converted to its hydrochloride salt in npropyl alcohol solution. The resulting 3-(m-anisyl)-3- carboxytropane hydrochloride had the M.P. 215-2175 C. (uncorn) when recrystallized from an n-propyl alcohol-ether mixture.

Anal.Calcd. for C H NO .HCl: Cl, 11.37. Found: Cl, 11.14.

3-(m-anisyl)-3-carboxytropane can be converted to 3- (m-hydroxyphenyl)-3-carboxytropane [X; R is CH R is OH] by refluxing it with aqueous hydrogen bromide and neutralizing the excess acid, according to the manipulative procedure given belowin Example 90.

l3 EXAMPLE 16 3-(m-Anisyl)-3-Carbeth0xytropane Hydrobromide [I; R is CH R is OCT-I R is C H A solution of 0.18 g. of 3-(m-anisyl)-3-carboxytropane in absolute ethanol was refluxed in a slow stream of dry hydrogen chloride for fifteen hours. After removal of the solvent under vacuum, the residue was dissolved in water, the solution made basic with dilute sodium hydroxide and the product extracted with methylene dichloride. The extracts were dried and concentrated giving 3-(m-anisyl)-3-carbethoxytropane in the form of an oil which was converted to its hydrobrornide salt and crystallized from an ethanol-ether mixture giving 3-(manisyl)-3-carbethoxytropane hydrobromide, MP. 178- 180 C. (uncorn).

Anal.Calcd. for C H NO HBr: C, 56.25; H, 6.82. Found: C, 55.66; H, 6.64.

By replacement of the (3-m-anisyl)-3-carboxytropane in the preceding preparation by a molar equivalent amount of 3-(m-hydroxyphenyl)-3-carboxytropane, there can be obtained 3-(m-hydroxyphenyl)-3-carbethoxytropane [1; R is CH R' is OH, R is C H The latter compound can be reacted with acetic anhydride, caproyl chloride, succinic anhydride, fi-cyclopentylpropionyl chloride, benzyl chloride, 3,4,5-trimethoxybenzoyl chloride or phenylacetyl chloride, to give, respectively, 3-(m-acetoxyphenyl)-3-carbethoxytropane, 3 (rn-caproyloxyphenyl)-3-carbethoxytropane, 3 [In (fl-carboxypropionyloxy)phenyl]-3-carbethoxytropane, 3.- [m (B cyclopentylpropionyloxy)- phenyl] -3-carbethoxytropane, 3- (m-benzoyloxyphenyl -3- carbethoxytropane, 3 [m-(3,4,S-trimethoxybenzoyloxy)- phenyl] 3 carbethoxytropane, or 3-(m-phenylacetoxyphenyl)-3-carbethoxytropane.

EXAMPLE 17 3 (m hydroxyphenyl) 3 (m hydroxybenzoyl)tro pane [VIII; R is CH R is OH] can be prepared by refluxing 3-(m-anisyl)-3-(m-anisoyl)tropane (Example 13) with aqueous hydrogen bromide and neutralizing the excess acid, according to the manipulative procedure given below in Example 90.

EXAMPLE 18 3 (m hydroxyphenyl) 3 [(m hydroxyphenyl)isonitrosomethyl1tropane [IX; R is CH R is OH] can be prepared from 3-(m-hydroxyphenyl)-3-(m-hydroxybenzoyl)tropane and hydroxylamine hydrochloride in pyridine-alcohol solution according to the manipulative procedure described above in Example 14.

EXAMPLE 19 3-(m-hydroxyphenyl)-3-carboxytropane [X; R is CH R is OH] can be prepared from 3-(m-hydroxyphenyl)-3- [(m-hydroxyphenyl)isonitrosomethyl]tropane and acetic acid saturated with hydrogen chloride according to the manipulative procedure described above in Example 15.

EXAMPLE 20 3 (m hydroxyphenyl) 3 carbethoxytropane [1; R is CH R is OH, R is C H can be prepared from 3-(mhydroxyphenyl)-3-carboxytropane in absolute ethanol saturated with hydrogen chloride according to the manipulative procedure described above in Example 16.

thick, white slurry of cyanohydrin [111; R is H] was stirred for one hour at room temperature, collected by filtration,

l 4 pressed as dry as possible and then added immediately to two liters of concentrated hydrochloric acid with stirring and cooling to keep the temperature below 25 C. The reaction mixture was stirred at room temperature for fifteen hours and then concentrated under vacuum. The residue was dried by adding benzene and distilling off the benzene, and finally by heating the residue at C. and 3 mm. pressure. Esterification of the resulting 3-hydroxy- 3-carboxynortropane [IV; R is H] was accomplished by refluxing it with 2.5 liters of methanol for twenty hours, during the first five hours of which period a rapid stream of dry hydrogen chloride was passed into the boiling solution. The reaction mixture was evaporated under vacuum, the solid residue dissolved in 550 ml. of water, the solution filtered and the filtrate treated with 400 g. of solid potassium carbonate with cooling. The solid material which separated was extracted twice with a total volume of 1.5 liters of boiling chloroform. The extracts were dried and concentrated, giving 135 g. of nor-a-ecgonine methyl ester, MP. 142-146 C. (uncorr.). Additional ester was isolated by further addition of potassium carbonate to the aqueous phase; 28 g., MP. 137144 C. (uncorr.). A sample when recrystallized from ethyl acetate had the MP. 144-l47 C. (corr.).

Anal.Calcd. for C H NO C, 58.36; H, 8.16; N, 7.56. Found: C, 58.28; H, 8.14; N, 7.60.

(b) 3-(Diphenylhydroxymethy[)Norpseudotropine Hydrochloride [V1; R and R are H] A solution of 100 g. of nor-a-ecgonine methyl ester, prepared as described in Part a above, in 1.5 liters of tetrahydrofuran was added to a stirred solution of phenyllithium (prepared from 594 g. of bromobenzene and 52.5 g. of lithium wire) in 1.5 liters of ether under a nitrogen atmosphere during a period of thirty minutes. The mixture was stirred and refluxed for three hours and then stirred at room temperature overnight. Following the same work-up procedure as that described in Example 1 there was obtained 157 g. of 3-(diphenylhydroxymethyl)- norpseudotropine hydrochloride, which upon recrystallization from n-propyl alcohol had the MP. 259.5 C. (dec.) (corr.). The product was found to contain n-propyl alcohol of crystallization.

Anal.-Calcd. for C H NO .HCL% C H O: C, 68.93; H, 7.34; Cl, 9.69; C H O, 5.38. Found: C, 69.24, 68.93; H, 7.84, 7.53; Cl, 9.69; C H O, 5.38.

EXAMPLE 22 3-Phenyl-3-Benzoylnortropane [VIII; R and R are H] A stirred suspension of 10 g. of 3-(diphenylhydroxymethyl)norpseudotropine hydrochloride (Example 21) in 30 ml. of acetic anhydride was treated all at once with 20 g. of fused, powdered zinc chloride. The temperature of the reaction mixture was kept at 15 C. for a few minutes and then stirred at room temperature for fifteen hours. The dark brown solution was then poured into 200 ml. of water, a few ml. of concentrated hydrochloric acid was added and the solution warmed on a steam bath until the odor of acetic anhydride was no longer detectable. The latter solution was made strongly acid with concentrated hydrochloric acid and the insoluble material which separated was extracted with methylene dichloride. The extracts were washed With sodium carbonate solution, dried and concentrated. The residue was recrystallized from ml. of n-propyl alcohol, giving 4.2 g. of 3-phenyl-3- benzoylnortropane, M.P. 209-2l2 C. (uncorr.).

Anal.--Calcd. for C H NO: C, 82.43; H, 7.27; N, 4.81. Found: C, 82.56, 82.70; H, 6.94, 7.33; N, 4.78.

The hydrochloride salt of 3-phenyl-3-benzoylnortropane had the M1. 290291.5 C. (dec.) (corr.) when recrystallized from an n-propyl alcohol-ether mixture.

Anal.--Calcd. for C H NOHCl: C, 73.27; H, 6.77; Cl, 10.82. Found: C, 73.38; H, 6.66; Cl, 10.84.

15 EXAMPLE 23 (a) 8-Cyano-3-Phenyl-3-Benzoylnortr0pane [VIII; R is CN, R is H] To a stirred solution of 7.1 g. of cyanogen bromide in 100 ml. of benzene at 50-55 C. was added over a period of three hours a solution of 10.0 g. of 3-phenyl-3-benzoyl tropane in 250 ml. of benzene. The reaction mixture was stirred at 50-55 C. for two hours longer and allowed to stand overnight at room temperature. The reaction mixture wasfiltered to remove a small amount of crystalline material and the filtrate was evaporated to dryness under vacuum. The residue was recrystallized from 100 ml. of methanol giving 5.7 g. of 8-cyano-3-phenyl-3-benzoylnortropane, M.P. 160.5162.5 C. (corr.) when recrystallized again from methanol. I

Anal.-Calcd. for C H N O': C, 79.71; H, 6.37; N, 8.86. Found: C, 79.66; H, 6.33; N, 8.67.

(b) 3-Phenyl-3-Benz0yln0rtr0pane [VIII; R and R are H] A mixture of 1.0 g. of 8-cyano-3-phenyl-3-benzoylnortropane, obtained as described in Part a above, and 50 ml. of concentrated hydrochloric acid was refluxed for seven hours. The reaction mixture was concentrated to approximately two-thirds the original volume under vacuum and made basic by treatment with excess solid potassium carbonate. The oily product which separated was extracted with methylene dichloride, and the extracts dried and concentrated. The residue was recrystallized from acetone and then twice from absolute alcohol, giving 3-phenyl-3-ber1zoylnortropane, M.P. 208212 C., identical by mixed melting point and infrared comparison with the product obtained above in Example 22.

EXAMPLE 24 3-Phenyl-3- (Phenylisonitrosomethyl)Nortropane Hydrochloride [IX; R and R are H] A mixture of 10.0 g. of 3-phenyl-3-benzoylnortropane (Examples 22, 23), 10.0 g. of hydroxylamine hydrochloride, 35 ml. of pyridine and 250 m1. of n-propyl alcohol was refluxed for sixteen hours. The reaction mixture was concentrated under vacuumand the residue crystallized from 25 ml. of water to give 10.5 g. of 3-phenyl-3-(phenylisonitrosomethyl)nortropane hydrochloride, M.P. 286 C. (dec.) (uncorr.) when recrystallized from Water.

Anal-Calcd. for C H N O.HCl: C, 70.06; H, 6.76; N, 8.17. Found: C, 69.95; H, 7.34; N, 7.94.

EXAMPLE 25 3-Phenyl-3-Carboxynortropane Hydrochloride [X; R and R are H] A suspension of 3.0 g. of 3-phenyl-3-(phenylisonitrosomethyl)nortropane hydrochloride (Example 24) in 50 ml. of acetic acid was heated on a steam bath for five hours, and a slow stream of dry hydrogen chloride was passed into the reaction mixture during this period. The preparation was worked up according to the manipulative procedure described above in Example 5, giving 1.5 g. of 3-phenyl-3-carboxynortropane hydrochloride, M.P. 275-276.5 C. (dec.) (corr.) when recrystallized from a methanol-ether mixture.

Anal.-Calcd. for C H NO HCI: C, 62.80; H, 6.78; Cl, 13.24. Found: C, 62.81; H, 6.88; Cl, 13.18.

EXAMPLE 26 3-Phenyl-3-Carbethoxynortropane HydrOchloride [I; R and R are H, R is C H A suspension of 6.0 g. of 3-phenyl-3-carboxynortropane hydrochloride (Example 25) in 300 ml. of thionyl chloride was refluxed for seventy-five minutes. The reaction mixture was concentrated in vacuo on a water bath, care being taken that the temperature did not rise above about 30 C. The residue was warmed with a small amount of absolute ethanol and then ether was added to cause separation of 5.8 g. of 3-phenyl-3-carbetlioxynortropane hydrochloride, M.P. 219.5-2215 C. (dec.) (corr.) when recrystallized from an ethanol-ether mixture.

Anal.-Calcd. for C H NO HCl: C, 64.96; H, 7.50; Cl, 11.99. Found: C, 64.85; H, 7.15; Cl, 12.07.

Alternatively, the esterification was carried out by treatment of the 3-phenyl-3-carboxynortropane with alcoholic hydrogen chloride at room temperature for several days.

EXAMPLE 27 8-Allyl-3-Phanyl-3-Carbcthoxyn rn'opane Hydrochloride [1; R is CH =CHCH R is H, R" is C H A mixture of 4.6 g. of 3phenyl-3-carbethoxynortropane hydrochloride (Example 26), 1.86 g. of allyl bromide, 6.6 g. of sodium carbonate and ml. of n-butyl alcohol was refluxed for seventeen hours. The reaction mixture was concentrated to dryness under vacuum, the residue shaken with water and methylene dichloride, and the aqueous phase extracted twice with methylene dichloride. The combined methylene dichloride extracts were dried and concentrated to give an oily residue which was converted to its hydrochloride salt, giving 4.5 g. of 8-allyl-3- phenyl 3 carbethoxynortropane hydrochloride, M.P. 193.5194 C. (dec.) (corr.) when recrystallized from an isopropyl alcohol-ether mixture.

Anal.Calcd. for C H NO .HCl: C, 67.94; H, 7.80; CI, 10.56. Found: C, 67.77; H, 7.79; CI, 10.34.

EXAMPLE 28 8-propargyl-3phenyl-3-carbethoxynortropane [I; R is CHECCH R is H, R is C H can be prepared by replacement of the allyl bromide in Example 27 by a molar equivalent amount of propargyl bromide.

EXAMPLE 29 8 [2- (p-aminophenyl)ethyl]-3-phenyl-3-carbethoxynortropane [1; R is p-H NC H CH CH R is H, R is C H can be prepared by replacement of the allyl bromide in Example 27 by a molar equivalent amount of 2-(p-aminophenyl)ethyl chloride.

EXAMPLE 30 8 benzyl-3-phenyl-3-carbethoxynortropane [I; R is C H CI-l R is H, R is C H can be prepared by replacement of the allyl bromide in Example 27 by a molar equivalent amount of benzyl bromide.

EXAMPLE 31 8 (3-phenylpropyl)-3-phenyl-3-carbethoxynortropane [I; R is C H CH CH CH R is H, R" is C H can be prepared by replacement of the allyl bromide in Example 27 by a molar equivalent amount of 3-phenylpropyl chloride.

EXAMPLE 32 8 [Z-(p-methoxyphenyl)ethyl]-3-phenyl-3-carbethoxynortropane [1; R is p-CH OC H CH CH R is H, R is C H can be prepared by replacement of the allyl bromide in Example 27 by a molar equivalent amount of 2- (p-methoxyphenyl) ethyl chloride.

EXAMPLE 33 8 [2- (p-chlorophenyl)ethyl]-3-phenyl-3-carbethoxynortropane [1; R is p-ClC H CH CH R is H, R is C H can be prepared by replacement of the allyl bromide in Example 27 by a molar equivalent amount of 2- (p-chlorophenyl) ethyl chloride.

EXAMPLE 34 8-cyclopropyl-3-phenyl-3-carbethoxynortropane [1; R

17 is C H R' is H, R is C H can be prepared by replacement of the allyl bromide in Example 27 by a molar equivalent amount 'of cyclopropyl bromide.

EXAMPLE 35 8-ethyl-3-phenyl-3-carbethoxynortropane [1; R is C 31 R is H, R is C H can be prepared by replacement of the allyl bromide in Example 27 by a molar equivalent amount of ethyl bromide.

EXAMPLE 37 8-(3,3-diphenyl-3-cyanopropyl)-3-phenyl-3-carbethoxynortropane [1; R is (C H C(CN)CH CH R is H, R" is C H can be prepared by replacement of the allyl bromide in Example 27 by a molar equivalent amount of 3,3- diphenyl-B-cyanopropyl bromide.

. EXAMPLE 38 8-Cinnamyl-3-Carbethoxy-3-Phenylnortropane M ethanesul fonate A mixture of 5.8 g. of 3-phenyl-3-carbethoxynortropane hydrochloride (Example 26), 3.8 g. of cinnamyl bromide, 7.2 g. of sodium carbonate and 200 ml. of nbutyl alcohol was refluxed for sixteen hours. Following the manipulative procedure described above in Example 27, the product was obtained in the free base form as an oil. The latter Was taken up in ether and treated with a slight excess of methanesulfonic acid which was crystallized from acetone and then twice from an isopropyl alcohol-ether mixture to give 8-cinnamyl-3-carbethoxy-3-phenylnortropane methanesulfonate in the form of colorless needles, M.P. 178-1805 C. (corn).

Anal.-Calcd. for C25H29NO2.CH3SO3HZ C, H, 7.05; S, 6.80. Found: C, 66.26; H, 7.33; S, 6.78.

EXAMPLE 39 8-(2-Phenylamin0ethyl)-3-Phenyl-3-Carbethoxynortropane p-Toluenesulfonate A mixture of 4.3 g. of 3-phenyl-3-carbethoxynortropane hydrochloride (Example 26), 4.0 g. of Z-phenylaminoethyl bromide hydrobromide, 6.0 g. of sodium carbonate and 100 ml. of n-butyl alcohol was refluxed for fifteen hours. Following the manipulative procedure described above in Example 27, the product was obtained in the free base form as an oil. An acetone solution of the latter was treated with a slight excess of p-toluenesulfonic acid inalcohol. Addition of ether gave a gum which was crystallized from acetone and then recrystallized twice from n-propyl alcohol, giving 8-(2-pheny1- aminoethyl) 3 phenyl 3 carbethoxynortropane ptoluenesulfonate in the form of colorless blades, M.P. 194-l95 C. (uncorr.).

Anal.-Calcd. for CZ4H3ONZOZQC7H8SO3Z N, 5.09. Found: N, 4.94.

EXAMPLE 4O 8-(n-0ctyl) -3-Phenyl-3-Carbethoxyn0rtropane Hydrochloride [1; R is n-C H R is H, R" is C H A mixture of 5.0 g. of 3-phenyl-3-carbethoxynortr0- pane hydrochloride (Example 26), 3.4 g. of n-octyl bromide, 3 g. of sodium carbonate and 50 ml, of n-butyl alcohol was refluxed for fifteen hours. The reaction mixture was Worked up by the manipulative procedure described above in Example 27 and the product isolated in the form of the hydrochloride salt, giving 4 g. of 8- (n octyl) 3 phenyl 3 carbethoxynortropane hydrochloride, M.P. 1388-1460 C. (corn) when recrystallized from a carbon tetrachloride-ether mixture.

Anal.-Calcd. for C H NO HCI: C, 70.65; H, 9.39; Cl, 8.69. Found: C, 70.74; H, 9.11; Cl, 8.57.

EXAMPLE 41 8 (n amyl) 3 phenyl 3 carbethoxynortropane hydrochloride [1; R is n-C H R is H, R" is C H was prepared from 3.0 g. of 3-phenyl-3-carbethoxynortropane hydrochloride, 1.6 g. of n-amyl bromide, 2 g. of sodium carbonate and 50 ml. of n-butyl alcohol according to the manipulative procedure described above in Example 27. There was thus obtained 2.6 g. of 8-(n-amyl)-3-phenyl-3- carbethoxynortropane hydrochloride, M.P. 148.6-155.4 C. (corn) when recrystallized from carbon tetrachloride.

Anal.Calcd. for C H NO .HCl: C, 68.92; H, 8.82; Cl, 9.69. Found: C, 68.67; H, 8.72; Cl, 9.44;

EXAMPLE 42 S-(Z-Phenylethyl)Nor-a-Ecgonine Methyl Ester Hydrochloride [V; R is C H CH CH lower-alkyl is CH A solution of 1.7 g. of nor-u-ecgonine methyl ester (Example 21), 1.9 g. of 2-phenylethyl bromide and 2.0 g. of potassium acetate was refluxed for four and one-half hours. The solvent was evaporated under vacuum and the residue heated at C. and 0.3 mm. to remove last traces of solvent. The residue was stirred with water and extracted With ether. The ether extracts were dried and concentrated and the product converted to the hydrochloride salt, giving 1.6 g. of S-(Z-PhEDYlCihYDnOf-ocecgonine methyl ester hydrochloride, M.P. 223229 C. (dec.) (corn) when recrystallized from an ethanol-ether mixture.

Anal.Calcd. for C H NO HCI: C, 62.66; H, 7.42; Cl, 10.88. Found: C, 62.40; H, 7.30; Cl, 10.80.

EXAMPLE 43 8-propargylnor-a-ecgonine methyl ester [V; R is CHECCH can be prepared by replacement of the 2- phenylethyl bromide in Example 42 by a molar equivalent amount of propargyl bromide.

EXAMPLE 44 8 [2 (p aminophenyl)ethyl]rior a ecgonine methyl ester [V; R is p-H NC H CH CH can be prepared by replacement of the 2-phenylethyl bromide in Example 42 by a molar equivalent amount of 2-(paminophenyl) ethyl chloride.

EXAMPLE 4s 8 benzylnor oc ecgonine methyl ester [V; R is C H CH can be prepared by replacement of the 2- phenylethyl bromide in Example 42 by a molar equivalent amount of benzyl bromide.

EXAMPLE 46 8 (3 phenylpropyl)nor a ecgonine methyl ester [V; R is C6H5CH2CH2CH2] can be prepared by replacement of the 2-phenylethyl bromide in Example 42 by a molar equivalent amount of 3-phenylpropyl chloride.

8- (Z-Phenylthyl) -3- (Diphenylhydroxymeihyl) N orpseudotropine Hydrochloride [VI; R is c mcu crr R is H] A solution of 37 g. of 8-(2-phenylethyl)nor-a-ecgonine methyl ester (Example 42) in 500 ml. of ether was added to 'a stirred solution of phenyllithium (prepared from 157 g. of bromobenzene and 13.9 g. of lithium Wire) in 1 liter of ether over a period of fifteen minutes; The mixture was stirred and refluxed for four hours andthen stirred overnight at room temperature; The reaction mixture was worked up according'to the manipulative procedure described above in Example 1, giving 405 g. of; 8 (2 phenylethyl) 3 (diphenylhydroxymethyl) norpseudotropine hydrochloride, M.P. 271.5-274" C. (dec.) (corn) after recrystallization from methanolether.

AnaL-Calcd. for C H NO .HCl: C, 74.73; H, 7.17; Cl, 7.89. Found: C, 74.88; H, 7.18; CI, 7.67.

EXAMPLE O 8 propargyl 3 (diphenylhydroxymethyl)norpseudotropine -[VI; R is CHECCH R is H] can be prepared by" replacement of the 8-(2-phenylethyl)nor-a-ecgonine methylester in Example 49by a molar equivalent amount of 8-pr0pargylnor-a-ecgonine methyl ester.

EXAMPLE 51 8 [2 (p aminophenyl)ethyl] 3 (diphenylhydi'oxymethyl) norpseudotropine [VI; R is V p-H NC H CH CH R is H] can be prepared by replacement of the 8-(2-phenylethyl) nor-a-ecgonine methyl ester in Example 49 by a molar equivalent amount of 8-[2-(p-aminophenyl)ethylJnorm-ecgonine methyl ester.

EXAMPLE 52 8 benzyl 3 (diphenylhydroxymethyl)norpseudotropine [VI; R is C H5CH R is H] can be prepared'by replacement of the- 8-(Z-phenylethyl)norx-ecgonine methyl ester in Ex-amp1e49 by a molar equivalent'amount.

of 8-benzylnor-a-ecgonine; methyl ester.

EXAMPLE 5 3 8 (3 phenylpropyl) 3- (diphenylhydroxymethyl) norpseudotropine [VI; R is C H CH CH CH R is H] can be prepared by replacement of the 8-(2-phenylethyl) nor-u-ecgonine methyl ester in Example 49 by a molar equivalent amount of '8-(3-phenylpropyl)nor-a-eegonine methyl ester.

EXAMPLE 54' (diphenylhydroxymethyl) norpseudotropine' hydrochloride (Example 49) in 250 ml. ofiacetic anhydride was treated all at once with. 35.5 .gof fused, powdered zinc chloride, and the mixture was: stirred at: room temperature for twenty hours. The reaction mixture was worked up ac- 5 cording to the manipulative procedure described above in Example 3,giving 28.0 g.- of 8-(2-phenylethyl)-3-phcnyl- 3-benzoylnortropane in the form of an oil, which after crystallization and recrystallization from hexane was obtained in the form of colorless needless, M.P. ll2l14 C. (uncorr).

Anai.Calccl. for :C H NOE. 3.53.

The hydrochloride salt ofi 8-(2-phenylethyl)-3-phenyl- 3-benzoylnortropane was prepared in the usual manner by treatment of an ethereal solution of the free base with an excess of ethanolic hydrogen chloride. The hydrochloride had the MP. 266-267" C. (dee) (HUGO-1T.) when recrystallized from absolute ethanol.

Arzai.-Calcdt for C H NOHCI: C, 77.85; H, 7.00; Cl, 8.21. Found: C, 77.80; H, 6.68; Cl, 8.13.

EXAMPLE57 8-propargyl-3phenyl-3-benzoylnortropane Will; R is N, 3.54. Found: N,

CIIECCIIZ, R is H] can be prepared by replacement of the 8-(2 phenylethyl). 3 (diphenylhydroxymethyl)norpseudotropine hydrochloride in Example 56 by a molar equivalent amount of 8-propargyl 3 (diphenylhydroxymethyl)norpseudotropine.

EXAMPLE 58 8-benzyl 3 phenyl- 3 benzoylnortropane [VIII; R is C H CH R is H] can beprepared by replacement of the 8-(2-phenylethyl) 3 (diphenylhydroxymethyl)norpseudotropine hydrochloride in Example 56 by a molar equivalent amount of. 8-benzyl-3-(diphenylhydroxymethyl)norpseudotropine.

EXAMPLE 60 8-(3-phenylpropy1) 3 phenyl 3 -benzoylnortropane [VIII; R is C H CH CH CH R. is H] can be prepared by replacement of the 8-(2-phenylethyl)-3-(dipheny1hydroxymethyl)norpseudotropine hydrochloride in: Example 5 6 by a molar equivalent amount of 8-(3-phenylpropyD-3- (diphenylhydroxymethyl)norpseudotropine.

EXAMPLE 61 8[Z-(p-methoxyphenyl)ethyl]-3 phenyl 3 benzoyl nortropane [Viiig R is p-CI-I OC H CH CH R'is H].

can be prepared by replacement of the 8-(2-phenylethyl)- 3 -.(diphenylhydroxymethyl)norpseudotropine hydrochlo ride in Example 56 by a molar equivalent amount ofi 8 [2 (p methoxyphenyDethyl] 3 (diphenylhydroxymethyl)norpseudotropine.

EXAMPLE 6'2 8- (Z-Plzenylelhyl) -3-Phenyl-3-(P/zenylfsonitrosomethyl A mixture of 2.0 g. of. 8-(2 phenylethyl1-3-phenyl1-3 h bath for fifteen hours.

benzoylnortropane hydrochloride (Example 56), 2.0 g. of hydroxylamine hydrochloride, 10 ml. of pyridine and 50 ml. of absolute ethanol was refluxed for fifteen hours. The crystalline material which had separated was collected by filtration and washed with water and with alcohol, giving 1.8 g. of 8-(2-phenylethyl)-3-phenyl-3-(phenylisonitrosomethybncrtropane hydrochloride, M.P. 313-3l5 C. (uncorr.) when recrystallized from dimethylformamide.

Anal.-Calcd. for C H N OHCI: C, 75.23; H, 6.99; Cl, 7.93. Found: C, 75140; H, 6.68; Cl, 7.91.

EXAMPLE 64 8-propargyl-3-phenyl 3 (phenylisonitrosomethyl)nortropane [IX; R is CHECCHZ, R is H] can be prepared by replacement of the 8-(Z-phenylethyl)-3-phenyl-3- benzoylnort-ropane hydrochloride in Example 63 by a molar equivalent amount of 8-propargyl-3-phenyl-3- benzoylnortropane.

EXAMPLE 65 S-[Z-(p-aminophenyl)ethyl] -3 phenyl 3 (phenylisonitrosomethyl)nortropane [.lX; R is p-H NC H CH CH R is H] can be prepared by replacement of the 8-(2- phenylethyl)-3-plienyl-3-benzoylnortropane hydrochloride in Example 63 by a molar equivalent amount of 8-[2-(paminophenyl ethyl] -3-phenyl-3-benzoylnortropane.

EXAMPLE 66 8- [2- (p-methoxyphenyDethyl] -3-phenyl-3 (phenylisonitrosomethyhnortropane [lXg R is p-CH C H CH CH R is H] can be prepared by replacement of the 8-(2-phenylethyl)-3-phenyl-3 -benzoylnortropane hydrochloride in Example 63 by a molar equivalent amount of 8-[2- (p-metlioxyphenyl ethyl] -3-phenyl-3-benzoylnortro pane.

EXAMPLE 69 S-[Z-(p-chlorophenyl)ethyl]-3-pheny1-3 (phenylisonitrosomethyl)nortropane [lX; R is p-ClC H Cl-l CI-I R is H] can be prepared by replacement of the S-(Z-phenylethyl)-3-phenyl 3 benzoylnortropane hydrochloride in Example 63 by a molar equivalent amount of S-[Z-(p-chlorophenyl) ethyl] -3 -phenyl-3 -benzoylnortropane.

EXAMPLE 70 8- (Z-Phenylethyl) -3-Phenyl-3-Carboxynortropane Hydrochloride Asuspension of 6 g. of 8-(2-phenylethyl)-3-phenyl-3- (phenylisonitrosomethyl)nortropane hydrochloride (Example 63) and 75 ml. of acetic acid was saturated with dry hydrogen chloride at 0 C. The reaction mixture was enclosed in a pressure bottle and heated on a steam The mixture was worked up according to the manipulative procedure described above in Example giving 4.6 g. of 8-(2-phenylethyl)-3-phenyl-3- carboxynortropane hydrochloride, M.P. 224224.5 C. (uncorr.) When recrystallized from a methanol-ether mixture. 1

Or C22H25NO2.HC1I C, H, Cl, 9.53; N, 3.77. Found: C, 70.87; H, 6.99; Cl, 9.37; N, 3.81.

EXAIMPLE 71 8-propargyl-3-phenyl 3 carboxynortropanc [X; R is CHECCH R is H] can be prepared by replacement of the 8-(2-phenylethyl) 3 phenyl-3-(phenylisonitrosm methyl)nortropane hydrochloride in Example 70 by a molar equivalent amount of 8-propargyl-3-phenyl-3- (phenylisonitrosemethyl}nortropane.

EXAMPLE 7 2 8-[Z-(p-aminophenyl)ethyl] 3 phenyl-3-carboxynortropane [X; R is p-H NC H CH CH R is H] can be prepared by replacement of the 8-(Z-phenylethyl)-3-phenyl- 3 (phenylisonitrosomethyl)nortropane hydrochloride in Example 70 by a molar equivalent amount of 8-[2-(paminophenyDethyl] 3 phenyl 3 (phenylisonitrosomethyl)nortropane.

EXAMPLE 73 8-benzyl 3 phenyl 3 carboxynortropane [X; R is C H CH R is H] can be prepared by replacement of the 8-(2-phenylethyl) 3 phenyl-3-(phenylisonitrosomethyhnortropane hydrochloride in Example 70 by a molar equivalent amount of 8-benzyl-3-phenyl-3-(phenylisonitrosomethyl)nortropane.

EXAMPLE 74 8-(3 phenylpropyl)-3-phenyl-3-carboxynortropane [X; R is C H CH CH CH R is H] can be prepared by replacement of the 8-(Z-phenylethyl)-3-phenyl-3-(phenylisonitrosomethyl)nortropane hydrochloride in Example 79 by a molar equivalent amount of 8-(3-phenylpropyl)- 3-phenyl-3- (plienylisonitrosomethyl) nortropane.

EXAMPLE 75 8-[2 (p-methoxyphenyl)ethyl] 3 phenyl-3-carboxynortropane [X; R is p-CH OC H CH CH R is H] can be prepared by replacement of the 8-(2-phenylethyl)-3- phenyl-3-(phenylisonitrosornethyl)nortropane hydrochloride in Example 70 by a molar equivalent amount of 8- [Z-(p-rnethoxyphenyl)ethyl]-3-phenyl 3 (phenylisono nitrosornethyl)nortropane.

EXAMPLE 76 8-[2-(p-chlorophenyDethyl] 3 phenyl-3-carboxynortropane [X; R is p-ClC H CH CH R is H] can be prepared by replacement or" the 8-(Z-phenylethyl)-3-pheny1- 3 (phenylisonitrosomethyl)nortropane hydrochloride in Example 70 by a molar equivalent amount of 8-[2-(pchlorophenyl)ethyl] 3 phenyl 3 (phenylisonitrosomethyl)nortropane.

EXAMPLE 77 8-(2-Phenylethyl)-3-Phenyl-3-Carbethoxynortropane Hydrochloride [1; R is C H CH CH R is H, R" is 0 m A mixture of 3.3 g. of 8-(2-phenylethyl)-3-phenyl-3- carboxynortropane hydrochloride (Example 70) and ml. of absolute ethanol was saturated with dry hydrogen chloride at 0 C. and kept at room temperature for six days. Evaporation of the solvent and recrystallization of the residue from a methanol-ether mixture, using activated charcoal for decolorizing purposes, gave 2.3 g. of 8-(2 phenylethyl)-3-phenyl-3-carbethoxynortropane hydrochloride, M.P 198-1995 C. (corn).

Anal.-Calcd. for C H NO HCl: C, 72.07; H, 7.56; Cl, 8.87. Found: C, 72.07; H, 7.55; CI, 9.05.

EXAMPLE 78 8-Cinnamylnor-ot-Ecgonine M ethyl Ester p-Toluenesulfonate [V; R is C H CH=CHCH lower-alkyl is CH A mixture of 6.0 g. of nor-a-ecgonine methyl ester Example 21), 6.4 g. of cinnamyl bromide, 3.2 g. ofpotassium acetate and 50 'ml. or n-butyl alcohol was refluxed for two and one-half hours. The reaction mixture was worked up according to the manipulative procedure described above in Example 42. The product was isolated in the free base form as an oil which was dissolved in acetone and treated with a slight excess of p-toluenesulfonic acid in ethanol, giving 6.0 g. of 8-cinnamylnor-aecgonine methyl ester p-toluenesulfonate, M.P. 20l-202 C., after two recrystallizations from isopropyl alcohol.

Anal.-Calcd. for C H NO C H SO C, 63.40; H, 6.60; S, 6.77. Found: C, 63.58; H, 6.79; S, 6.97.

EXAMPLE 79 3-Phenyl-3-(Phenylhydroxym ethyl) Tropane {XI; R is CH R is H] (A)- BY LITHIUM ALUMINUM HYDRIDE REDUCTION OF 3-PHENYL-3-BENZOYLTROPANE To a warm, stirred suspension of 0.5g. of lithium aluminum hydride in-75 ml. of ether was added all at once 2.0 g. of 3-phenyl-3-benzoyltropane (Example 3) in 100 ml. of ether, and the mixture wasrefluxed for six hour. The mixture was cooled, and the excess lithium aluminum hydride was decomposed by dropwise addition of 1 ml. of water followed by 1 ml. of 35% sodium hydroxide solution. The solid material which had formed was collected by filtration and extracted once with boiling chloroform. The chloroform extracts were dried and concentrated,.giving 2.1 g. of 3-phenyl-3-(phenylhydroxymethyl)tropane, M.P. 160161 C. (corn) when recrystallized from carbon tetrachloride.

Anal.-Calcd. for C I-I NO: C, 82.01; H, 8.20; N, 4.56. Found: C, 82.36; H, 8.55; N, 4.52.

The. methiodide salt of 3-phenyl-3-(phenylhydroxymethyl)tropane was prepared by treatment of an acetonitrile solution of the free base with an excess of methyl iodide. 'Ihe methiodide had the M.P. 280282.5 C. (corn).

Anal.-Calcd. for C H NOI: C, 58.80; H, 6.28; I, 28.24. Found: C, 58.85; H, 6.01; I, 28.10.

.The methiodide of 3-phenyl-3-(phenylhydroxyrnethyD- tropane was found to have an anticholinergic activity 3.8% that of atropine sulfate. Its intravenous toxicity in mice (ALD was 8.0 mg./kg. of body weight.

(B) BY CATALYTIC HYDROGENATION OF 3PHENYL-3 BENZOYLTROPANE A- solution of 8.8 g. of 3-phenyl-3-benzoyltropane in 225 ml. of ethanol wasshaken with 0.6 g. of platinum oxide catalyst and hydrogen at room temperature until oneequivalent of hydrogen was taken up. The catalyst was removed by filtration, the filtrate evaporated to dryness and the residue recrystallized from acetone, giving 6.5 g. of 3-phenyl-3-(phenylhydroxymethyl)tropane.

EXAMPLE 80 d-carbamylpseudotropine [XII; R is CH To a solution of sodium amide, which had been prepared from 14 g. of sodium and a few crystals of ferric nitrate in 1 liter of liquid ammonia, was added 20 g. of a-ecgonine methyl ester. The reaction mixture was stirred at room temperature until the ammonia had evaporated, and the residue was decomposed by dropwise addition of 120 ml. of water. The aqueous phase was saturated with solid potassium carbonate and extracted several times with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give a colorless crystalline residue, The residue was triturated with 150 ml. of absolute ether to give 16.0 g. of 3- carbamylpseudotropine, M.P. 155.8-159.2 C. (corr.).

Anal.'--Calcd. for C l-1 N C, 58.68; H, 8.76; N, 15.21. Found: C, 58.85; H, 8.69; N, 15.19.

, addition of 150 ml. of water.

EXAMPLE 81 3-Propionylpseudqtropine [Xillg R is CH R is C H To a stirred solution of ethyhnagnesium bromide, prepared from368 g. of ethyl bromide and 82.2 g. of magne sium in 2 liters of ether, was added a solution of 62.1 g. of 3-carbamylpseudotropine in 500 ml. of tetrahydrofuran. The resulting mixture was stirred and refluxed for fifteen hours and then decomposed by the dropwise addition of 340 ml. of concentrated hydrochloric acid. After standing for three hours at room temperature, the aqueous phase was made basic with an excess of solid potassium carbonate, and the solid which precipitated was collected by filtration and extracted twice with 3 liter portions of boiling chloroform. The aqueous filtrate was extracted five times with chloroform. The combined chloroform extracts were dried over anhydrous sodium sulfate and concentrated to yield 72 g. of crystalline solid. The latter was extracted with 1.5 liters of boiling hexane, and concentration of the extracts and cooling caused separation of 29.5 'g. of 3-propionylpseudotropine, M.P. 120.6123.4 C. (corn) when recrystallized from hexane.

AiZfll.-Ct1d. for C H NO C, 66.97; H, 9.71; N, 7.10. Found: C, 67.29; H, 9.61; N, 6.94.

EXAMPLE 82 3-(Ethylphenyllzydroxymethyl) Pseudotropine H ydrochloride [XIV;R is CH R is H, R is C 11 To a solution of phenyllithium, prepared from 31.4 g. of hromobenzene and 2.8 g. of lithium wire in 500 ml. of ether, was added all at once a warm solution of 4.0 g. of 3-propionylpseudotropine in ml. of tetrahydrofuran. After stirring and refluxing for one and one-half hours, thereaction mixture was cooled and hydrolyzed by the The aqueous phase was extracted twice with ether, and the ether extracts were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was dissolved in methylene dichloride, the solution dried over anhydrous sodium sulfate and concentrated to give 6.5 g. of a light yellow oil which crystallized upon standing at room temperature. The latter was dissolved in acetone and a slight excess of alcoholic hydrogen chloride was added. The

EXAMPLE 83 3-Phenyl-B-Propionyltropane Hydrochloride [XV; R is CH R is H, R' is C H A solution of 3.3 g. of 3-(ethylphenylhydroxymethyl)- pseudotropine hydrochloride and 15 g. of fused, powdered zinc chloride in 30 ml. of acetic anhydride was stirred at room temperautre for fifteen hours. The reaction mixture was poured into an excess of cold aqueous sodium hydroxide and the product was extracted with methylene dichloride. The extracts were dried and concentrated, and the residue was dissolved in 30 ml. of acetone and treated with an excess of alcoholic hydrogen chloride, wheerupon there separated 2.2 g. of 3-phenyl-3- propionyltropane hydrochloride, M.P. 273.2275.8 C. (corn) when recrystallized from a methanol-ether mixture.

Anal.-Calcd. for C H NOHCl: C, 69.49; H, 8.23; Cl, 12.07. Found: C, 69.26; H, 8.06; Cl, 12.02.

EXAMPLE 84 3-phenyl-3-(l isonitrosopropyl)tropane [XVL R is CH R is H, R is C H can be prepared by heating a solution of 3-phenyl-3-propionyltropane hydrochloride with hydroxylamine hydrochloride in a pyridine-ethanol solution according to the manipulative procedure described above in Example 4.

EXAMPLE 85 3-phenyl-3-carboxytropane hydrochloride [X; R is CH R is H, B-series] can be prepared by heating 3- phenyl-3-(l-isonitrosopropyl)tropane hydrochloride with acetic acid saturated with hydrogen chloride according to the manipulative procedure described above in Example 5. The product obtained is identical with that obtanied in Example 5.

EXAMPLE 86 3- [Ethyl (m-Anisyl )Hydroxymethyl]Pseudotropine Hydrochloride rxrv; R is CH3, R is on a'" is (3 1-1 To a stirred solution of m-anisylmagnesium bromide prepared from 118 g. of m-bromoanisole and 15.3 g. of magnesium in 1 liter of ether under nitrogen was rapidly added a solution of 15.0 g. of 3-propionyipseudotropine in 250 ml. of tetrahydrofuran. The reaction mixture was refluxed and stirred for three hours, left at room temperature for fifteen hours and then poured into a cold solution of 66 ml. of concentrated hydrochloric acid in 400 ml. of water. The aqueous phase was made basic with solid potassium carbonate, and the inorganic salts were removed by filtration and washed with methylene dichloride. The filtrate was extracted with methylene dichloride and the combined methylene dichloride washings and extracts were dried and concentrated in vacuo. The residue was dissolved in acetone and treated with an excess of ethanolic hydrogen chloride whereupon there separated 14.5 g. of 3-[ethyl(m-anisyl)hydroxymethyl]- pseudotropine hydrochloride, M.P. 245-2455 C. (dec.) (uncorr.) after recrystallization from a methanol-ether mixture.

AnaL-Calcd. for C13HZI1NO3.HCIZ C, 63.23; H, 8.25; Cl, 10.37. Found: C, 63.59; H, 8.17; Cl, 10.15.

EXAMPLE 87 3-(m-anisyl)-3-propionyltropane hydrochloride [XV; R is CH R is OCH R is C 11 was prepared from 14.2 g. of 3-[ethyl(m-anisyl)hydroxymethyl]pseudotropine h drochloride and 28.4 g. of zinc chloride in 280 ml. of acetic anhydride according to the manipulative procedure described above in Example 83. There was thus obtained 7.9 g. of B-(m-anisyl)-3-propionyltropane hydrochloride, M.P. 237.5-238.5C. (uncorn) when recrystallized first from a methanol-ether mixture and then from an isopropyl alcohol-ether mixture.

Anyl.-Calcd. for C H NO .HCl: C, 66.75; H, 8.09; Cl, 10.95. Found: C, 66.94; H, 8.07; Cl, 10.97.

EXAMPLE 88 3-(m-anisyl)-3-( l-isonitrosopropyl)tropane hydrochloride [XVI; R is CH R is OCH R' is C H can be prepared by heating 3-(m-anisyl)-3-propionyltropane hydrochloride and hydroxylamine hydrochloride in pyridine-ethanol solution according to the manipulative procedure described above in Example 4.

EXAMPLE 89 S-(m-anisyl)-3-carboxytropane hydrochloride [X; R is CH R is OCH can be prepared by heating 3-(manisyl)-3 (1 isonitrosopropyl)tropane hydrochloride in acetic acid saturated with hydrogen chloride according to the manipulative procedure described above in Example 15. The product obtained is identical with that obtained in Example 15.

EXAMPLE 90 S-(m-Hydroxyphenyl)-3-Propi0nyltropane Hydrochloride [XV; R is CH R is OH, R' is C H A solution of 1 g. of 3-(m-anisy1) -3-propionyltropane fim hydrochloride in 25 ml. of 48% aqueous hydrobromic acid was refluxed for twenty minutes under nitrogen. The

reaction mixture was concentrated to dryness in vacuo, and the residue was dissolved in ml. of water. The latter solution was made basic by addition of 4 ml. of 35% sodium hydroxide solution and extracted with ether. The aqueous phase was acidified with concentrated bydrochloric acid and then saturated with solid potassium carbonate. The resulting mixture was extracted with chloroform, and the chloroform extracts were dried and concentrated. The residue was dissolved in acetone, decolorized with activated charcoal and treated with ethanolic hydrogen chloride, whereupon there separated 0.78 g. of 3-(m-hydroxypheny)-3-propionyltropane hydrochloride, M.P. 274.2-275.8 C. (corr.) when recrystallized from an ethanol-ether mixture.

Anal.Calcd. for C H NO .HCl: C, 65.90; H, 7.81; CI, 11.44. Found: C, 66.23; H, 7.81; Cl, 11.25.

This application is a division of our copending application, Serial No. 731,857, filed April 30, 1958.

We claim:

1. A compound selected from the group consisting of (A) compounds having the formula wherein R is a member of the group consisting of hydrogen, lower-aliphatic hydrocarbon, monocarbocyclic aryllower-aliphatic hydrocarbon, and monocarbocyclic aryl amino lower aliphatic hydrocarbon, the monocarbocyclic aryl in each instance being selected from the group consisting of phenyl and phenyl substituted by from one to three substituents selected from the group consisting of hydroxy, fiuoro, chloro, bromo, iodo, nitro, amino, loweralkoxy and lower-alkylamino; R is a member of the group consisting of hydrogen and lower-alkoxy; and Y is a member of the group consisting of 3-R-phenyl and lower-alkyl; (B) acid-addition salts thereof; and (C) lower-alkyl, lower-alkenyl and monocarbocyclic aryllower-alkyl quaternary ammonium salts thereof.

2. 3-(diphenylhydroxymethyl)pseudotropine.

3. An acid-addition salt of 3-(diphenylhydroxymethyl) pseudotropine. I v

4. 3- di (m-anisyl hydroxymethyl] pseudotropine.

5. An acid-addition salt of 3-(diphenylhydroxymethyl) norpseudotropine.

6. An acid-addition salt of 8-(2-phenylethyD-3-diphenylhydroxymethyl norpseudotropine.

7. 3-(ethylphenylhydroxymethyl)pseudotropine.

8. 3- [ethyl-(3-methoxyphenyl hydroxymethyl] pseudotropine.

9. The process for preparing a compound having the formula which comprises reacting a S-hydroxy-S-carbo-loweralkoxy-S-R-nortropane of th formula with a compound selected from the group consisting of phenyllithium and 3-R-phenylmagnesium halide, wherein R is a member of the group consisting of hydrogen, lower-aliphatic hydrocarbon, monocarbocyclic aryl-loweraliphatic hydrocarbon, and monocarbocyclic arylaminolower-aliphatic hydrocarbon, the monocarbocyclic aryl in each instance being selected from the group consisting of -27 phenyl and phenyl substitutedby, from one to three substituents selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, nitro, amino, lower-alkoxy and lower-alkyiaminopR is amember of the groupconsisting of hydrogensand lower-.alkoxy; and Y is 3-R- phenyl. V

10. The process for preparing a compound having the formula t. which comprises reacting a 3-hydroxy-3 lower-alkanoyl- 8-R-nortropane of the formula CHr-CH-CH: OH

CHPCH-6H 00R" with a compound selected from the group consisting of phenyllithium and 3-R'-phenylmagnesium halide, where.- in R is a member of the group consisting of hydrogen, lower aliphatic hydrocarbon, monocarbocyclic aryl- 28 lower-aliphatic hydrocarbon, andrmonocarbocyclic arylamino-lower-aliphatio hydrocarbon, the monocarbocyclic aryl in each instance being, selected from the group consisting of phenyl and phenyl substituted by from one to three substituents selected from the group consisting of References Cited in the file of this patent UNITED STATES PATENTS 2,800,480 Zirkle July 23, 1957 FOREIGN PATENTS 644,115 Great Britain Oct. 4, 1950 OTHER REFERENCES Cope et al.: J. Am. ChemfSoc, Vol. 73, pages 3419- 3424 (1951).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION ,ill NO. 07 ,3 9 January 15, 1963 Sydney Archer et al.

It is hereby certified that error appears in the above numbered patnnt requiring correction and that the said Letters Patent should read as worrected below.

Column 1, lines 22 to 27, the formula should appear as shown below instead of as in the patent:

column 2, lines 35 to 38, formula IV should appear as shown below instead of as in the patent:

column 5, line 19, for "XVIII" read VIII; column 8, line 44, for "C H NO:" read C H NOI column 13, line 25, for "benzyl" read benzoyl Signed and sealed this 17th day of December 1963.

(SEAL) Attest:

ERNEST W. SWIDER EDWIN L. REYNOLDS Attesting Officer Acting Commissioner of Patents UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,073,829 January 15, 1963 Sydney Archer et al.

It is hereby certified that error appears in the above numbered patant requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 22 to 27, the formula should appear as shown below instead of as in the patent:

column 2, lines 35 to 38, formula IV should appear as shown below instead of as in the patent:

CH "H H I R C coon CH CH CH column 5, line [19 for "XVIII" read VIII; column 8, line 44 for "C H NO:" read C H NO: column 13, line 25, for "benzyl" read benzoyl Signed and sealed this 17th day of December 196 (SEAL) Attest:

ERNEST W. SWIDER EDWIN L. REYNOLDS Attesting Officer Acting Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) COMPOUND HAVING THE FORMULA 